Effects of psychotropic drugs on the thrombin-induced liberation of arachidonate in human platelets.
OBJECTIVE
To compare the effects of chlorpromazine (CPZ), prochlorperazine (PCP), trifluoperazine (TFP), clozapine (CLO), haloperidol (HPD), quetiapine (QTP), pimozide (PMZ), and olanzapine (OLP) as well as the tricyclic antidepressants amitriptyline AMI, imipramine IMI, and nortriptyline NTP on thrombin-induced liberation of arachidonic acid AA in platelets.


METHODS
This work was carried out at the Department of Biomedicine, University of Bergen, Norway in 2006-2007. Human platelets pre labelled with [3H] arachidonate were incubated with thrombin in the absence and presence of the drugs, and the amount of free [3H] arachidonate liberated was determined. Myosin light chain (MLC) phosphorylation was determined in [32P] phosphate-labelled platelets after sodium dodecyl sulfate polyacrylamide gel electrophoresis. The effects of the drugs on the molecular area and surface pressure of phospholipid monolayers were determined in the Langmuir apparatus.


RESULTS
All drugs reduced arachidonate liberation with the ranking order of increasing potency: OLP<QTP<HPD<AMI<IMI<PMZ<NTP<CPZ<TFP<PCP. Since phenothiazines are calmodulin antagonists, this property of the drugs was tested as reduction of thrombin-induced phosphorylation of MLC in [32P] Pi-labelled platelets. Only PCP, CPZ, TFP, and NTP reduced MLC phosphorylation. All 11 drugs studied markedly increased the mean molecular area of dipalmitoyl phosphatidylserine monolayers at 37 degrees.


CONCLUSIONS
The mechanisms for reduction of arachidonate liberation is thought to interfere with activation of cytosolic phospholipase A2 (cPLA2) by alteration of the PLA2 phospholipid substrate structure in platelet membranes.
Oruch
Ramadhan
R
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. ramadhan.oruch@biomed.uib.no
Pryme
Ian F
IF
Holmsen
Holm
H
D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D016718:Arachidonic Acid / Q000096:biosynthesis*; D001792:Blood Platelets / Q000187:drug effects*; D002478:Cells, Cultured; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D013917:Thrombin / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; D008563:Membrane Lipids; D018994:Myosin Light Chains; D016718:Arachidonic Acid; D054513:Group IV Phospholipases A2; D013917:Thrombin